INNOVATION AND IMPROVEMENT 

COMMITTED TO A DIVERSIFIED AND LONG-TERM R&D+i APPROACH

Grifols has been firmly committed to innovation. The company allocated EUR 291 million in R&D+i in 2018, denoting a 9.4% increase over the previous year.

The company continues to bolster its innovation strategy through the Grifols Innovation Office and reinforce its portfolio of research projects via diverse acquisitions. Of note is the 51% stake acquired in MedKeeper, a U.S. technology supplier of IT solutions designed to optimize the efficiency and safety of hospital pharmacy systems. The agreement includes a call option to purchase the remaining 49% within a three-year timeframe.

One of the company’s most significant milestones in 2018 was the October release of the topline results of the AMBAR (Alzheimer Management by Albumin Replacement) clinical trial. The findings indicated a significant slowdown in the progression of Alzheimer’s in patients in moderate stages of the disease, symbolizing a capstone moment in Grifols’ 15 years of AD research.

GRIFOLS’ R&D+i AT A GLANCE

INTEGRATED APPROACH AND EFFECTIVE R&D+i MANAGEMENT

GRIFOLS’ INNOVATION IN HEALTH AND HEALTHCARE TECHNOLOGY ALLOWS IT TO IMPROVE THE HEALTH AND WELL-BEING OF PEOPLE

At the forefront of innovation, Grifols has been shaping and contributing to the plasma derivatives sector for more than 75 years. The company’s path-breaking fractionation system and nano-filtration method surpass the highest standards of compliance in the production of plasma-derived medicines. Grifols also stands out for its sterile filling method – now an industry standard – and as one of the first companies to implement double viral inactivation processes in the manufacture of factor VIII.

Grifols’ integrated R&D+i strategy merges in-house initiatives with projects in investee companies that whosed research projects complement its own.

The integrated strategy and the long-term vision of Grifols’ R&D+i led to it distinction in “2018 Global Innovation 1000” among the top 1,000 global companies that most invest in research and innovation. The report is published annually by Strategy&, a global consulting subsidiary of PwC.

GRIFOLS’ MAIN INNOVATION OBJECTIVES

A ROBUST STRATEGY THAT COMBINES INTERNAL AND EXTERNAL INVESTMENTS

GROUNDED ON A SUSTAINABLE AND LONG-TERM VIEW, GRIFOLS’ COMMITMENT TO R&D+i IS AN INTRINSIC PART OF ITS PIONEERING SPIRIT

Grifols promotes a comprehensive R&D+i strategy by investing in internal and external projects. Third-party investments and collaborations represent an extension of its internal R&D+i efforts.

This holistic approach is articulated through the Grifols Innovation Office, responsible for evaluating and expediting the research, development and commercialization of innovative treatments, products and services. It also promotes the ongoing improvement of existing products and operations, as well as promotes collaborations with key innovation players in academic and research fields.

Grifols Innovation Office coordinates the initiatives of the group’s various functional areas. In this role, it prepares and presents projects before interdisciplinary committees comprised by members of Grifols senior management. These committees conduct thorough and rigorous analyses to identify, evaluate and prioritize new opportunities.

THE CREATION OF VÍCTOR GRÍFOLS I LUCAS FOUNDATION BIOETHICS CHAIR UNDERSCORES THE IMPORTANCE THE COMPANY GIVES TO THE ETHICAL IMPACT OF ITS PROJECTS

Grifols established the Scientific Review Board in 2018 in order to bolster its innovation efforts. The Board supervises and assesses the progress of internal research projects from a technical vantage point, as well as analyzes the potential value-added of research opportunities in Grifols’ investees. This cross-functional committee comprised by senior executives of the Grifols Innovation Office, corporate divisions and clinical R&D areas.

This committee reflects the effort of Grifols not only in the review, supervision and coordination of in-house and external research project, but also in the collaboration and promotion of synergies among the main research areas and divisions group’s divisions.

The analyses and recommendations made by the interdisciplinary committees and Scientific Review Board are presented to the Board of Directors, which is the ultimate decision-making body with regard to innovation investments.

The Grifols Innovation Office includes Grifols Innovation and New Technology (GIANT), responsible for channeling the group’s investments in R&D+i companies and related projects; the Scientific and Medical Affairs area; and the Department of Patents and Trademarks.

AMBAR’S RESULTS ARE VERY ENCOURAGING AND INSPIRE GRIFOLS TO PURSUE THIS LINE OF RESEARCH

THE AMBAR STUDY

AMBAR is an international and multicenter clinical trial designed by Grifols in collaboration with the Fundació ACE in Barcelona and Alzheimer’s Disease Research Center at the University of Pittsburgh (United States). After a successful pre-clinical trial and completion of phases I and II, the research team commenced the phase II/ IIIb phase to determine whether plasma exchange could slow down the progression of the disease.

The clinical trial lasted 14 months and had two different phases: an initial phase for all patients and an another phase in which patients received differing levels of albumin. In some cases, patients received albumin modified with IGIV to compensate for a possible decrease in endogenous immunoglobulins. The placebo arm received a simulation of plasma exchange in both phases.

The analysis of the results obtained in the clinical trial was performed on the total study population and included the assessment of the differences to placebo in the primary outcomes of the following study arms: a) three combinations of plasma exchange with albumin and IGIV replacement that shared the same volume of plasma removed (plasmapheresis) regardless of the arm, b) an arm with all patients treated with plasma exchange, and c) an arm that included all patients treated with plasma.

Grifols plans to offer updates for the remainder of 2019, specifically at the AAIC (Alzheimer’s Association International Conference) in Los Angeles (USA) in July and at the CTAD (Clinical Trials on Alzheimer’s Disease) in San Diego (USA). In December, all the analyses mentioned in the study will be available.

AMBAR IS AN INNOVATIVE TREATMENT APPROACH AIMED AT REDUCING THE PROGRESSION OF ALZHEIMER’S DISEASE THROUGH REGULAR PLASMA EXCHANGES

For more information on the AMBAR study visit: https://www.grifols.com/en/ambar

CLINICAL TRIAL DESIGN

PLASMA EXCHANGE WITH ALBUMIN AS A THERAPY

The AD patients who took part in the AMBAR clinical trial were treated with regular plasma exchanges, a safe and proven therapy based on the plasmapheresis technique.

Plasma exchange consists of extracting blood from the patient and fractionating the cellular components of plasma in a plasmapheresis machine. Following fractionation, the plasma is replaced by albumin (in most cases) and reintroduced into the patient along with the other cellular components.

Requiring no anesthesia, the treatment is generally administered in hospitals or outpatient centers to treat a variety of blood, neurological and autoimmune diseases.

CONGRESS CTAD - OCTOBER 2018 – BARCELONA TOPLINE RESULTS DEMOSTRATED EFFICACY OF AMBAR IN SLOWING DOWN THE PROGRESSION IN MODERATE AD PATIENTS

Grifols presented AMBAR (Alzheimer Management by Albumin Replacement) topline results (phase IIb/III) at the “Clinical Trials on Alzheimer’s Disease” (CTAD) congress.

Results in the pre-specified cohort of moderate AD patients demonstrated a statistically significant reduction of 61% in disease progression from baseline across both primary efficacy endpoints as measured by the Alzheimer’s Disease Assessment Scale-cognitive (ADAS-Cog) and the Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) scales.

While a consistent delay in the progression of disease was observed in the treatment arms for the pre-specified mild cohort (the placebo arm presented a similar pattern), and the difference did not reach statistical significance.

In the three-combination arms, the differences to placebo showed between 50 and 75% less decline for the ADAS-Cog scale in the treated patients and between 42 and 70% less decline for the ADCS-ADL scale. In the arm with all patients treated with plasma exchange, the difference to placebo achieved a 66% less decline for the ADAS-Cog scale in the treated patients with a statistical significance and a 52% less decline for the ADCS-ADL scale with a statistical significance.

CONGRESS AD/PD - MARCH 2019 – LISBON NEW DATA EXTENDS THE EFFICACY OF AMBAR TO PATIENTS WITH MILD AD

The latest results presented at the 14th International Congress on Alzheimer’s and Parkinson’s (AD/PD) indicate AMBAR’s efficacy extends to both patients with moderate AD, as well as those in the mild stages.

These additional results complement and confirm those presented in October and from these results we can deduce a relationship between the response of patients and the dose of albumin and immunoglobulin used in protein replacement after the plasmapheresis treatment.

Of the three different treatment arms, and in view of the analyzed data, it appears that the most effective treatment is the one combining the highest doses of albumin and intravenous immunoglobulin.

A positive effect of the treatment is observed in all the cognitive aspects analyzed so far in the clinical trial, for all patients, both mild and moderate, treated as a whole. In addition, in some relevant areas, such as language and processing speed, not only is a slowdown in disease progression demonstrated, but there is a statistically significant improvement compared to patients in the placebo group, who exhibit the impairment of the disease itself. Also, in patients with moderate phases of the disease who were analyzed separately, the area that presents more positive results is memory. Patients with mild phases of the disease show clear improvements in language and processing speed.

AMBAR IS BASED ON A DUAL-ACTION MECHANISM: BETAAMYLOID CIRCULATES IN PLASMA BOUND TO ALBUMIN. PLASMAPHERESIS FLUSHES OUT BETA-AMYLOID AND REPLACES IT WITH ALBUMIN, A WIDELY USED PROTEIN WITH BINDING, ANTIOXIDANT AND IMMUNODULATORY PROPERTIES

R&D+i BY DIVISION

BIOSCIENCE DIVISION

Grifols’ leadership in the plasma proteins sectors is driven by a robust R&D+i program that promotes research on new therapeutic indications for plasma-derived products and continuous development of innovative production methods that enhance the efficiency and safety of Grifols products.

MAIN MILESTONES IN 2018

  • Completion of the clinical research phase of a new 20% subcutaneous immunoglobulin to treat patients with primary immunodeficiencies. The product has been submitted to the FDA for marketing authorization.
  • Development of a predictive model for population pharmacokinetics (PopPK) to administer subcutaneous immunoglobulin in patients with primary immunodeficiencies, which would inform the proper dosing of this plasma-derived product and guide its treatment usage.
  • Development of Gamunex® studies as maintenance therapy for myasthenia gravis (MG). The company plans to submit the application for EMA marketing authorization in 2019. 
  • Development of the phase III PRECIOSA trial on the potential benefits of albumin to treat liver cirrhosis, as well as the phase III APACHE trial to treat acute-on-chronic liver failure (ACLF) with albumin.
  • Albumin’s new flexible packaging format is currently in the registration stage. 
  • Approval and launches of new formulations that expand Grifols’ product portfolio and treatment alternatives for patients and healthcare professionals:
    • FDA approval of a new alpha-1 antitrypsin liquid formulation (Prolastin®-C Liquid).
    • FDA approval of a new intramuscular immunoglobulin formulation (GamaSTAN®) for immediate protection against hepatitis A and measles. 
    • FDA approval of a new anti-rabies immunoglobulin formulation (HyperRAB®) to treat patients exposed to the rabies virus.

The following table summarizes Grifols’ R&D+i projects over the last three years and their development phase:

GRIFOLS AND THE REPUBLIC OF LIBERIA, IMPORTANT INROADS ON THE DEVELOPMENT OF ANTI-EBOLA IMMUNOGLOBULINS

In 2014, Grifols launched a non-profit initiative to produce anti-Ebola immunoglobulin to treat affected populations in West African countries. The project’s research forms part of a long-term clinical trial to evaluate whether plasma from healthy Ebola survivors can boost the immune response in afflicted patients and help them overcome the disease. Grifols fully financed the project, which included the collaboration of the Liberian government, the FDA, the World Health Organization (WHO) and various NGOs. 

AS A RESULT OF ITS STRATEGIC R&D+i APPROACH, GRIFOLS IS THE ONLY COMPANY POSITIONED IN THE THREE TECHNOLOGIES WITH THE POTENTIAL TO LEAD THE TRANSFUSION DIAGNOSTICS MARKET, WHICH WOULD PROVIDE A KEY DIFFERENTIATING FACTOR AND UNIQUE STANDING IN THE FIELD

DIAGNOSTIC DIVISION

The Diagnostic Division’s R&D+i initiatives aim to enhance the safety of blood transfusions through the development of comprehensive solutions that add value throughout the value chain, from donations to transfusions. Their efforts primarily focus on offering new systems and technologies, including new reagents and analyzers.

In the field of specialty diagnostics – an area with a high potential for growth – Grifols produces genomic and proteomic tests for in-vitro diagnostics, prognosis assessment, response prediction and biologic drug monitoring. It also develops molecular diagnostic and prognosis tests for oncology, autoimmunity, cardiovascular medicine and the central nervous system.

MAIN MILESTONES IN 2018

  • The division efforts to innovate and expand its product portfolio led to six FDA approvals, including a test used to detect RNA specific for the Zika virus (Procleix® Zika Virus); a test to detect HIV and hepatitis B and C (Procleix® Ultrio Elite); and a West Nile virus detection test (Procleix® WNV). In the blood-typing line, of note is the FDA approval for the conventional antiserums line and the diagnostic ID CORE XT, used to genotype blood groups.
  • FDA submission of the blood test to detect the babesiosis parasite (Procleix® Babesia). Approval is expected in the first quarter of 2019 although the test is currently available as an IND (Investigational New Drug).
  • Clinical trials on the Procleix® Ultrio Elite line continue in China.
  • In specialty diagnostics, clinical trials continue in the U.S. to expand the portfolio of coagulation products and instruments, as well as those in the Promonitor® line to monitor biologic drugs.
  • In the last quarter of the year, the FDA also approved the new mid-sized and totally automated analyzer, Erytra Eflexis®.
  • The company continues to expand its portfolio of recombinant proteins

GRIFOLS PROMOTES THE DEVELOPMENT OF SOLUTIONS TO AUTOMATE HOSPITAL PHARMACY SERVICES

HOSPITAL DIVISION

The Hospital Division’s R&D projects aim to expand the range of hospital logistics systems and compounding processes for hospital pharmacies, as well as provide hospitals with intravenous solutions.

MAIN MILESTONES IN 2018

  • Grifols’ Pharmatech line, which includes hospital logistics, continues to focus its efforts on developing new prototypes in its Gri-fill® line, specifically those used in the preparation of intravenous mixtures; improvements in the Kiro-Oncology robot; and the initial stages of development of a totally automated robot used to prepare non-hazardous compounds.
  • The acquisition of MedKeeper reinforces the Pharmatech line and development of solutions to automate hospital pharmacy services.
  • Two new products were submitted for FDA approval: a physiological saline solution in a needle-free Fleboflex® container, which, in addition to enhancing the product portfolio, can be utilized in Kiro-Grifols robotics; and an anticoagulant in a bag format that will be used in Grifols’ plasma centers and expand the third-party product portfolio.
GRIFOLS ENGINEERING

Grifols Engineering offers services and internal support to develop and build the group’s manufacturing plants. It represents a clear differentiating factor and source of added value by helping the group maximize its productivity.

The company also develops innovative engineering projects and custom solutions for third parties. Its portfolio of services includes consulting, engineering processes, feasibility studies, construction of start-up services and machinery design, and construction of specialized equipment for fractionation, purification and sterile filling lines.

RESEARCH IN GRIFOLS’ INVESTEES

Grifols considers its alliances and investments in investees and external research projects as extensions of its internal R+D+i efforts, allowing the company to foster and share knowledge with renowed global researchers.

AlbaJuna Therapeutics (Spain): Development of a new treatment strategy based on monoclonal antibodies to neutralize HIV. Their efforts in 2018 centered on identifying a candidate that would allow them to commence pre-clinical regulatory development in 2019.

Alkahest (United States): Research on the benefits of plasma proteins to treat agerelated cognitive impairment. In 2018, the company initiated two clinical trials on patients with moderate and severe Alzheimer’s disease using a fraction of plasma.

Araclon (Spain): Specialized in the research, treatment development and diagnostic tests for Alzheimer’s disease and other neurodegenerative diseases. It began its phase II clinical trial on an Alzheimer’s vaccine in 2018.

GigaGen (United States): Research and development of new recombinant immunoglobulins using immune system cells. In 2018, the company began development on a hyperimmune polyclonal immunoglobulin using human biological samples to treat an infectious disease.

Singulex (United States): Development of an innovative ultrasensitive technology SMC™ (Simple Molecular Counting), with broad clinical diagnostic and transfusion applications. This technology enables high-value assays using rare biomarkers.

SUPPORTING GLOBAL RESEARCH 

RESEARCH AWARDS: GRIFOLS SCIENTIFIC AWARDS

The Grifols Scientific Awards underscore the company’s long-standing commitment to the global research community. These recognitions promote and distinguish research in areas related to Grifols’ core business.

* There were no GATRAs granted in 2018.

For more information on award criteria, candidates, application process and past winners, please visit http://www.grifolsscientificawards.com

GRIFOLS OFFERS AWARDS AND SCHOLARSHIPS IN SUPPORT AND RECOGNITION OF THE SCIENTIFIC COMMUNITY AND ITS RESEARCH

GRIFOLS CHAIR FOR THE STUDY OF CIRRHOSIS

In 2015, Grifols established The Grifols Chair for the Study of Cirrhosis, a private chair with a global reach aimed at generating research and education on liver diseases, particularly cirrhosis. The Grifols Chair and the European Consortium for the Study of Chronic Liver Failure are led and coordinated by Prof. Vicente Arroyo through a newly created independent European Foundation for the Study of Chronic Liver Failure (EF-Clif).

SPONSORING RESEARCH INITIATIVES: THE ISR PROGRAM

Grifols supports and promotes research that broadens the body of scientific knowledge on plasma proteins through the Investor-Sponsored Research Program, or ISR.

MEDICAL SCHOLARSHIPS: ENHANCING THE PROFESSIONAL DEVELOPMENT OF HEALTHCARE PROVIDERS

The Grifols North America Medical Education Grants program supports independent medical-education activities designed to advance the professional development of healthcare providers.

RESEARCH PUBLICATIONS

The company also promotes the generation of knowledge internally. The work of Grifols’ scientists and researchers have featured prominently in a number of publications, including:

PATENTS AND TRADEMARKS

GRIFOLS PROTECTS THE INTELLECTUAL PROPERTY OF ITS MAIN PRODUCTS THROUGH PATENT OWNERSHIP, CO-OWNERSHIP AND LICENSING

AN INTERNATIONAL TEAM OF EMPLOYEES FROM SPAIN, IRELAND AND THE UNITED STATES IS RESPONSIBLE FOR MANAGING PATENT AND TRADEMARKS APPROVALS, OVERSEEING THEIR IMPLEMENTATION AND MONITORING POSSIBLE VIOLATIONS

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